*Vrije Universiteit Brussel, ^#Vanderbilt University and ^&Women’s Health Alliance, Nashville TN

Synonyms: Ectrodactyly (non-specific term meaning congenital absence of fingers or toes)

Definition: Split-hand/split-foot malformation (SHFM) is a limb malformation involving the central rays of the autopod (the distal division of the limb such as the foot or hand) and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals and metatarsals.

Etymology: The term ectrodactyly is derived from Greek ektroma = abortion and daktuloz  = finger

Prevalence: 0.1:10,000 (Birch-Jensen, 1949)

Etiology: Four loci for split hand –split foot malformation (SHFM) have been mapped:

• SHFM1 on chromosome 7q21,
• SHFM2 on chromosome Xq26,
• SHFM3 on chromosome 10q24 and
• SHFM4 recently found to be caused by mutations in the p63 gene, a homologue of the archetypal tumor suppressor TP53, on chromosome 3q27. (1,2)

Features of genetic interest include:

• autosomal dominant inheritance,
• incomplete penetrance with skipped generations,
• 2 or more affected offspring of normal parents, suggesting autosomal recessive inheritance,
• X-linked inheritance,
• anomalous segregation ratios in offspring of affected males.

Pathogenesis: The apical ectodermal ridge is a critical signaling center that directs the outgrowth and patterning of the developing limb. The fundamental developmental defect  is a failure of the apical ectodermal ridge to maintain this activity i.e. the differentiation throughout the limb bud.

Sonographic findings: The two typical manifestions are the lobster-claw variety (absence of central rays, hand divided into 2 parts by a cone-shape cleft tapering proximally; the 2 parts of the hand can be apposed like a lobster claw) and monodactyly type (deficiency of radial rays, only the fifth digit remains).

Detection rate: A study undertaken in 12 European countries investigated the detection rate of limb reduction deficiencies between 1996-1998. The same methodology of registries were used. The report demonstrated a detection rate of isolated limb reduction defects of 24.6% compared with 49.1% for associated malformations. The prenatal detection rate of limb reduction deficiencies varied in relation with the ultrasound screening policies from 20.0% to 64.0% in countries with at least one routine fetal scan.(3)

Case report:

A 32-year-old patient was seen in her fifth pregnancy for her routine scan at 12.5 weeks of gestation.

Her past medical history was uneventful. Past surgical history included an appendectomy, right oophorectomy and diagnostic laparoscopy. In her past obstetric history we noted 2 missed abortions with D&C at the age of 21 and 23. One year later she suffered a premature labor after premature rupture of the membranes at ± 24 weeks of gestation. At  the age of 28 she underwent another D&C for a missed abortion of a twin pregnancy at 11.5 weeks of gestational age. The current pregnancy was conceived after in-vitro fertilization with expected delivery date of August  29^th. She was administered Progesteron IM twice a day, Aspirine and Fragmin? twice a day.

There are 2 video clips of the left arm (1.6 MB)  and legs (1.1 MB) which demonstrate the findings better then the images below.

The first set of images are the left arm of the baby (the right side presents similar findings). The images demonstrate a paucity of fingers with fused fingers. The common name of this is "lobster-claw" deformity, and the medical term is ectrodactyly.

The second set of images are the left leg of the baby, and the right. Similar findings are observed at this level

.

The sonogram demonstrated a fetus with CRL of 58mm and a malformation of both hands and feet. There was a very deep cleft in the palm of both hands. The same clefting was present at the level of the feet. More detailed scanning one week later confirmed these findings. There were no facial abnormalities nor other associated anomalies.

The patient mentioned that her husband had a syndactyly of the first and second toe of both feet. There were numerous members of her husbands’ family having syndactyly or split hand deformations. The patient was counseled about the severity of the malformations and was put in contact with surgeons to discuss the management of this condition.

Karyotyping was performed by chorionic villus sampling and revealed a normal male karyotype (46,XY with G-banding).

At 19.5 weeks of gestational age the patient was admitted at labor ward because of premature rupture of the membranes. The pregnancy was terminated by extra-amniotic prostaglandins.The patient delivered a male fetus with a length of 115 mm, head circumference of 135 mm and abdominal circumference of 115 mm. There was oligodactyly and syndactyly of both hands. There was also oligodactyly of both feet. No other anomalies could be observed.

The following are several images of different patients with split hand –split foot malformations:

• Ectrodactyly - ectodermal dysplasia – cleft syndrome: ectrodactyly, syndactyly of hands and feet, atypical anhidrotic ectodermal dysplasia, cleft lip with or without cleft palate; lacrimal duct abnormalities and urogenital abnormalities can be associated (4), as well as omphalocele and anal atresia (5,6). This syndrome is thus distinct because of the larger variety of organ systems that can be affected.
• Brachydactyly in particular type 1: limb defects are brachydactyly (short fingers), hypoplastic middle phalanges, hypoplastic/absent terminal phalanges, symphalangism, mild syndactyly and deformed thumbs and big toes. (2)
• Multiple synostoses syndrome: limb malformations are synostosis of elbows, fingers, wrist and foot; brachydactyly; absent/hypoplastic middle phalanges; absent/hypoplastic proximal interphalangeal flexion creases; short, broad metacarpals; radial head dislocation; abnormal toes; as well as absent /hypoplastic nails, thorax and nose deformities.(2)
• Amniotic band syndrome: asymmetrical, mostly random amputation without remodeling of the digits.
• Karsch-Neugebauer syndrome: split hand/split foot and congenital nystagmus; (7,8)
• Cleft hand and absent tibia syndrome: cleft hand, absent middle finger, flexed ring finger, absent tibia, absent forearm, tetramonodactyly, transverse hemimelia, hypoplastic big toes and cup-shaped ears.(2,9)
• Adams-Oliver syndrome: variable distal limb reduction abnormalities in conjunction with defects of the calvarium and scalp. (1)

Recurrence risk:

• SHFM1: autosomal dominant  with variable expressivity and incomplete penetrance = 50%
• SHFM2: X-linked = 50% in case of a boy
• SHFM3: possible autosomal dominant form unlinked to 7q21-q22 nor the X-linked form = 50%
• SHFM4: Not available.

Management: termination of pregnancy can be offered in view of the degree of the lesions, otherwise surgical management to pollicize a finger is performed.

References

1: Ianakiev P, Kilpatrick MW, Toudjarska I, Basel D, Beighton P, Tsipouras P. Split hand/split foot malformation is caused by mutations in the p63 gene on 3q27. Am J Hum Genet 2000;67(1):59-66

2: OMIM database 183600, 313350, 600095,  #605289, 129900, #186500, 119100, 602077, 112500

3: Stoll C, Wiesel A, Queisser-Luft A, Froster U, Bianca S, Clementi M. Evaluation of the prenatal diagnosis of limb reduction deficienties. Prenat Diagn 2000;20(10):611-8

4: Roelfsema NM, Cobben JM. The EEC syndrome: a literature study. Clin Dysmorphol 1996;5(2):115-27

5: De Smet  L,  Fryns JP. Anal atresia and abdominal wall defect as unusual symptoms in EEC syndrome. Genet. Counsel.1995;6:127-130

6: Majewski F, Goecke T. Rectal atresia as rare manifestation in EEC syndrome. Am J Med Genet 1996;63(1):190-2

7: Pilarsck RT,  Pauli RM, Bresnick GH, Lebovitz RM. Karsch-Neugebauer syndrome: Split foot /split hand and congenital nystagmus. Clin. Genet. 1985;27(1):97-101

8: Wong SC, Cobben JM, Hiemstra S, Robinson PH, Heeg M. Karsch-Neugebauer syndrome in two sibs with unaffected parents. Am J Med Genet 1998;75(2):207-10

9:  Majewski F,  Kuster W ,  ter haar B,  Goecke T. Aplasia of tibia with split-hand/ split foot deformity. Report of six families with 35 cases and considerations about variability and penetrance. Hum Genet 1985;70(2):136-47